NDT Advance Access originally published online on April 20, 2007
Nephrology Dialysis Transplantation 2007 22(7):1812-1815; doi:10.1093/ndt/gfm207
© The Author [2007]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
Contrast media nephropathy—how to diagnose and how to prevent?
Richard Solomon
Division of Nephrology and Hypertension, Fletcher Allen Health Care, University of Vermont School of Medicine, UHC 2309, 1 South Prospect St, Burlington, VT 05401, USA
Correspondence and offprint requests to: Richard Solomon, MD, Division of Nephrology and Hypertension, Fletcher Allen Health Care, University of Vermont School of Medicine, UHC 2309, 1 South Prospect St, Burlington, VT 05405, USA. Email: richard.solomon{at}vtmednet.org
Keywords: acute kidney injury; contrast media; haemodialysis; hydration; N-acetylcysteine
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Introduction
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An increasing number of individuals are being exposed to iodinated
contrast media (CM). This derives from both the technical advances
that have enhanced the role of imaging in the diagnostic and
therapeutic arena and the changing demographics of the population.
There are more elderly individuals with a burden of chronic
diseases including hypertension, diabetes, kidney disease and
heart disease, for which the tools of the radiologist and interventionalist
are particularly appropriate. It is therefore not surprising
that increasing attention in the medical literature is being
given to the renal adverse effect of CM, contrast-induced nephropathy
(CIN) and strategies to minimize its incidence.
Before attempting to synthesize from this literature a reasoned approach to the prevention of CIN, I would like to emphasize the pitfalls of this body of work. To begin with, a uniform definition of CIN does not exist. This is no small issue, as the incidence of CIN can vary 2-fold in the same population depending upon whether one uses an absolute increase in serum creatinine (
0.5 mg/dl increase) or a relative increase in serum creatinine (25% increase) or a combination of the two measured 48–72 h post-CM exposure. When a common definition of CIN is not used, comparisons between clinical trials are very difficult. Second, clinical trials in this area tend to be small and single centre (less than a few hundred patients). They often lump together patients with diverse risk factors, routes of CM administration, different types of CM and different reasons for imaging. Particularly in small trials, attempts to adjust for these confounders often lack sufficient power.
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Risk factors
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The incidence of CIN increases in patients with certain comorbities
such as impaired kidney function [estimated Glomerular filtration
rate (eGFR < 60 ml/min/1.73 m
2)], and impaired left
ventricular ejection fractions (<40%) [
1]. When diabetes
is present in addition to one of the above, the incidence of
CIN increases further [
2]. Based largely upon historical controls
and data extolling the benefit of intravenous fluids (see subsequently),
patients who are dehydrated or volume-depleted prior to CM administration
also have an increased risk of CIN. Finally, any condition that
impairs renal blood flow, such as hypotension, or Nonsteroidal
anti-inflammatory drugs, is also likely to increase the risk
of CIN [
3]. Therefore, the first step in designing strategies
to minimize the incidence of CIN is to correctly identify those
individuals at greatest risk. At the very least, this involves
calculating GFR using either the abbreviated modification of
diet in renal disease (MDRD) formula or the somewhat less accurate
Cockcroft–Gault formula and recording any history of heart
failure, diabetes, diuretic use or NSAID use.
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Prevention
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The next step is to correct any decreases in renal blood flow
by ensuring that intravascular volume is replete. This means
giving oral saline loading [
4] or intravenous fluids in high
risk patients and discontinuing diuretics immediately before
CM exposure. Many questions remain regarding when to start and
for how long to administer intravenous fluids, what type of
intravenous fluid to administer and whether the recommendations
hold for intravenous as well as intra-arterial administration
of CM.
There is a general consensus that for intra-arterial CM studies in high risk patients, intravenous fluids need to be started hours before CM exposure and continued for hours post-CM exposure [5]. Shortening the pre-contrast time for intravenous fluids comes at the expense of a greater rate of administration (up to 3 ml/kg/h for 1 h pre-CM). All the clinical trials involving administration of intravenous fluids have continued the fluids for a minimum of 6 h post-CM at 1 ml/kg/h. There is insufficient data regarding patients at high risk receiving intravenous CM. In a small study of 39 patients, Bader [6] found that intravenous fluids for 12 h before and after CM exposure resulted in a smaller fall in measured GFR and a lower incidence of CIN (5% vs 20%, P = NS) compared with a bolus of 300 ml of isotonic saline at the time of CM administration.
The type of intravenous fluids is also controversial. Mueller compared isotonic saline to hypotonic saline in 1620 low-risk patients undergoing cardiac angiography. Intravenous fluids were started on the morning of the angiography and continued at 1 ml/kg/h until the following morning. Those who received isotonic saline had a lower incidence of CIN (0.7% vs 2.0%). Interestingly, those patients with renal insufficiency did not have a reduction in the incidence of CIN with isotonic saline [7]. Another trial compared isotonic saline with oral water loading in low-risk patients undergoing angiography. Water loading was associated with an increased incidence of CIN compared with intravenous saline (35% vs 4%, respectively) [8]. However, water loading the night before followed by 6 h of intravenous fluids at 
4 ml/kg/h was as effective as 24 h of intravenous fluids at 1 ml/kg/h in high risk patients undergoing angiography [9]. Isotonic saline has also been compared with isotonic sodium bicarbonate in two trials [10,11]. Both found isotonic bicarbonate to be superior to sodium chloride in patients undergoing cardiac angiography, with and without the addition of N-acetylcysteine [10,11].
Finally, it should be noted that giving intravenous fluids usually increases urine output. However, increasing urine output pharmacologically with furosemide or mannitol has not been uniformly associated with a reduced incidence of CIN. Three prospective randomized trials have found the use of furosemide in addition to intravenous saline to result in a higher incidence of CIN compared with saline alone [4,12,13]. On the other hand, Stevens found that measures to increase urine flow, including mannitol and furosemide, were associated with a decrease in the incidence of CIN in those with urine outputs >150 ml/h [14].
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Anti-oxidants
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The use of antioxidant derives from our understanding of CIN
pathophysiology which highlights the role of reactive oxygen
species [
15]. The initial demonstration of a protective effect
of N-acetylcysteine (NAC) involved patients receiving intravenous
CM for abdominal CT exams [
16]. Subsequent use of NAC in patients
receiving intra-arterial CM found mixed results and a number
of meta-analyses could not uniformly support the use of this
agent [
17]. More recently, trials with higher doses of NAC have
been more encouraging [
1,
18]. A single trial with ascorbic acid
also found a benefit in predominately low-risk patients [
19]
while another trial found no benefit when added to NAC in high-risk
patients [
11].
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Vasodilators
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Trials employing vasodilators have produced generally negative
results. In some trials, vasodilator-induced systemic hypotension
may have contributed to a post procedure rise in serum creatinine
unrelated to CM exposure. Current interest has focused on targeted
renal therapy (TRT). Vasodilator drug is delivered directly
into the renal artery through a special bifurcating catheter
placed at the time of angiography. Higher doses of drug can
be administered without systemic side effects [
20]. Ongoing
trials in high-risk patients will be completed this year.
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Choice of contrast media
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The dose of CM administered is a generally accepted risk factor
for CIN. Dose is best calculated as the ratio of grams of iodine
per estimated GFR in millilitre per minute [
21]. A meta-analysis
comparing high- and low-osmolality CM conducted in the early
1990s found a lower incidence of CIN with low-osmolality CM
in patients with chronic kidney disease [
22]. A small clinical
trial comparing an iso-osmolality CM with a low osmolality CM
in high-risk patients also found a lower incidence of CIN with
the iso-osmolality agent [
23]. These two studies support the
concept of ‘osmotoxicity’ with the lowest incidence
of CIN seen when CM with the lowest osmolality are used. However,
multiple additional trials comparing iso-osmolality and low-osmolality
CM in high-risk populations, with both intravenous and intra-arterial
CM, have not been able to confirm these results [
24–27].
Rather these trials suggest that CM are nephrotoxic also by
virtue of other physiochemical properties and that osmolality
alone cannot explain the divergent results [
28].
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Removal of contrast media
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The use of haemodialysis to remove CM following its administration
in high risk patients has also been studied. Unfortunately,
trials with dialysis concurrent and following CM administration
have failed to find any benefit with regard to CIN [
29–32].
Dialysis is not able to remove CM quickly enough to prevent
the renal injury. In patients with severely impaired renal function
(eGFR < 30 ml/min), haemofiltration prior to CM administration
is reported to offer protection against both CIN and adverse
cardiovascular events [
33,
34]. However, since the definition
of CIN relies on changes in serum creatinine which are lowered
by the haemofiltration procedure, it is difficult to conclude
that haemofiltration prevents a true fall in GFR.
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Summary
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The literature leaves much room for continued controversy regarding
prevention of CIN. High-risk patients undergoing cardiac or
peripheral angiography should receive intravenous fluids for
at least 1 h before and 6 h after CM exposure. Sodium bicarbonate
may offer an advantage over sodium chloride solutions although
more data is required. ‘Double dose’ NAC may offer
better protection than single dose. A minimal dose of a CM with
a low incidence of CIN, but not necessarily a low osmolality,
should be used.
For patients receiving intravenous CM, including high-risk patients, there is even less data from which to make recommendations. Patients should be encouraged to drink water starting the day before the exam and, in high-risk patients, additional intravenous saline can be given in the immediate post-procedure period. The efficacy of anti-oxidant therapy needs to be confirmed by additional studies. Low volume of CM with a low incidence of CIN is encouraged.
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Acknowledgements
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Dr Solomon has received research grants from Bracco Diagnostics
and honoraria for educational activities from Bracco Diagnostics,
Berlex, Tyco-Mallinckrodt and Schering Pharmaceuticals.
Conflicts of interest statement. He is an advisory board member for Bracco Diagnostics and Tyco-Mallinckrodt.
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References
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Received for publication: 27. 2.07
Accepted in revised form: 16. 3.07
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Introduction
Risk factors